U.S. patent application number 12/933617 was filed with the patent office on 2011-05-05 for 2'-halobiphenyl-4-yl intermediates in the synthesis of angiotensin ii antagonists.
This patent application is currently assigned to LEK Pharmaceuticals D.D.. Invention is credited to Zdenko Casar, Anton Copar, Andrej Premrl.
Application Number | 20110105539 12/933617 |
Document ID | / |
Family ID | 40647168 |
Filed Date | 2011-05-05 |
United States Patent
Application |
20110105539 |
Kind Code |
A1 |
Copar; Anton ; et
al. |
May 5, 2011 |
2'-HALOBIPHENYL-4-YL INTERMEDIATES IN THE SYNTHESIS OF ANGIOTENSIN
II ANTAGONISTS
Abstract
A process for obtaining 2'-halo-4-methylbiphenyls is described,
which comprises reacting 4 halotoluene with a 1,2-dihalobenzene in
the presence of elemental metal such as magnesium, lithium or zinc,
wherein 0 to 0.9 molar, particularly 0 to 0.2 molar excess of
4-halotoluene in regard to 1,2-dihalobenzene is used, and arised
organometal intermediates are quenched by elemental mental halogen.
In addition, the coupling of arised 2'-halo-4-methylbiphenyls with
2-(1-propyl)-4-methyl-6-(1'-methylbenzimidazole-2-il)benzimidazole
to afford
3'-(2'-halo-biphenyl-4-ylmethyl)-1,7'-dimethyl-2'-propyl-1H,3'H-[2-
,5']bibenzoimidazolyl, which can be further converted to
organometallic compound and said organometallic compound is further
reacted with formic acid derivative, such as N,N-dimethylformamide,
alkylformiate or carbon dioxide to obtain telmisartan, is also
described. Further described is use of in line analytics for
monitoring the aforementioned reactions, process for preparing a
pharmaceutical composition and/or dosage for, or use in preparing a
medicament.
Inventors: |
Copar; Anton; (Ljubljana,
SI) ; Casar; Zdenko; (Ljubljana, SI) ; Premrl;
Andrej; (Ljubljana, SI) |
Assignee: |
LEK Pharmaceuticals D.D.
Ljubljana
SI
|
Family ID: |
40647168 |
Appl. No.: |
12/933617 |
Filed: |
March 19, 2009 |
PCT Filed: |
March 19, 2009 |
PCT NO: |
PCT/EP09/53267 |
371 Date: |
December 8, 2010 |
Current U.S.
Class: |
514/264.1 ;
436/98; 514/381; 514/394; 544/279; 548/252; 548/253; 548/305.4;
570/182; 570/204 |
Current CPC
Class: |
Y10T 436/147777
20150115; C07C 17/14 20130101; C07C 17/263 20130101; C07C 17/2632
20130101; C07D 235/20 20130101; A61P 9/12 20180101; C07C 17/14
20130101; C07C 17/2632 20130101; C07C 17/263 20130101; C07C 25/18
20130101; C07C 25/18 20130101; C07C 25/18 20130101 |
Class at
Publication: |
514/264.1 ;
548/305.4; 570/182; 570/204; 548/252; 548/253; 544/279; 436/98;
514/394; 514/381 |
International
Class: |
C07D 403/04 20060101
C07D403/04; C07C 25/18 20060101 C07C025/18; C07C 17/26 20060101
C07C017/26; C07D 403/10 20060101 C07D403/10; C07D 257/04 20060101
C07D257/04; C07D 471/04 20060101 C07D471/04; G01N 33/00 20060101
G01N033/00; A61K 31/4184 20060101 A61K031/4184; A61K 31/41 20060101
A61K031/41; A61K 31/519 20060101 A61K031/519; A61P 9/12 20060101
A61P009/12 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 20, 2008 |
EP |
08153084.2 |
Mar 20, 2008 |
EP |
08153085.9 |
Claims
1. A process for obtaining telmisartan or salt thereof, comprising
converting
3'-(2'-halo-biphenyl-4-ylmethyl)-1,7'-dimethyl-2'-propyl-1H,3'H-[2,5']bib-
enzoimidazolyl is converted to an organometallic compound and
reacting said organometallic compound with formic acid ester or
amide and oxidized, or with carbon dioxide.
2. The process according to claim 1, wherein formic acid ester or
amide is N,N-alkylformiate or dimethylformamide.
3. The process according to claim 1 or 2, wherein
3'-(2'-halo-biphenyl-4-ylmethyl)-1,7'-dimethyl-2'-propyl-1H,3'H-[2,5']bib-
enzoimidazolyl is converted with magnesium to Grignard reagent, or
with Grignard reagent by halogen/metal-exchange reaction to another
Grignard reagent, or with zinc to organozinc reagent; preferably or
is converted with lithium to organolithium reagent, or is converted
with organolithium reagent by halogen/metal-exchange reaction to
another organolithium reagent.
4. A process for obtaining
3'-(2'-halo-biphenyl-4-ylmethyl)-1,7'-dimethyl-2'-propyl-1H,3'H-[2,5']bib-
enzoimidazolyl comprising coupling
2-(1-propyl)-4-methyl-6-(1'-methylbenzimidazole-2-il)benzimidazole
and 4'-halomethyl-2-halo-biphenyl.
5. A compound of formula 4: ##STR00015## wherein A represents X,
Li, MgX or ZnX and X represents Cl, Br or I.
6. A compound selected from the group consising of
4'-bromomethyl-2-bromo-biphenyl, 4'-iodomethyl-2-iodo-biphenyl,
4'-iodomethyl-2-bromo-biphenyl, 4'-iodomethyl-2-chloro-biphenyl,
4'-chloromethyl-2-iodo-biphenyl, 4'-chloromethyl-2-bromo-biphenyl,
and 4'-chloromethyl-2-chloro-biphenyl.
7. A process for obtaining 2'-halo-4-methylbiphenyls, comprising
reacting a 4-halotoluene is r cted with a 1,2-dihalobenzene in the
presence of magnesium, lithium, zinc, cobalt, or copper, and
optionally a catalyst, wherein less than 1 molar excess of
4-halotoluene in regard to 1,2-dihalobenzene is used, and arisen
organometal intermediates are quenched by elemental halogen.
8. The process according to claim 7, wherein less than 0.9 molar,
0.2 molar excess of 4-halotoluene in regard to 1,2-dihalobenzene is
used.
9. The process according to claim 8, wherein proportionally for
each 1 mol of 1,2-dihalobenzene used less than 2.9 mol,
particularly from 1 to 2 mol; preferably 1 mol of elemental halogen
is used to quench the organometal intermediate.
10. The process according to claim 7, wherein the reaction is
carried out in ether solvent or in a mixture of aprotic solvents
comprising ether.
11. A process for the synthesis of a compound selected from the
group consisting of telmisartan, losartan, irbesartan, candesartan,
olmesartan, valsartan or tasosartan, a salt thereof, an ester
thereof and an amide thereof, comprising preparing
4'-halomethyl-2-halo-biphenyl according to claim 7 and converting
4'-halomethyl-2-halo-biphenyl to said compound.
12. The process of claim 1 further comprising monitoring the
reacting process with in line analytics.
13. The process in accordance with claim 12, wherein the reaction
is a Grignard reaction, and wherein in line analytics is FTIR and
one or more of the following peaks: 783 cm-1 and 1227 cm-1, 1035
cm-1, 880 cm-1, 695 cm-1 is monitored.
14. A process for obtaining a pharmaceutical composition and/or
dosage form comprising preparing telmisartan or salt thereof
according to claim 1; and mixing it, optionally in combination with
another active pharmaceutical ingredient, with pharmaceutical
excipient.
15. (canceled)
16. The process according to claim 8, wherein less than 0.2 molar
excess of 4-halotoluene in regard to 1,2-dihalobenzene is used.
17. The process according to claim 8, wherein proportionally for
each 1 mol of 1,2-dihalobenzene used, from 1 to 2 mol of elemental
halogen is used to quench the organometal intermediate.
18. The process according to claim 8, wherein proportionally for
each 1 mol of 1,2-dihalobenzene used, 1 mol of elemental halogen is
used to quench the organometal intermediate.
19. A process for obtaining a pharmaceutical composition and/or
dosage form comprising obtaining 2'-halo-4-methylbiphenyls
according to claim 7 and converting the 2'-halo-4-methylbiphenyls
to telmisartan and mixing said telmisartan, optionally in
combination with another active pharmaceutical ingredient, with
pharmaceutical excipient.
20. A process for obtaining a pharmaceutical composition and/or
dosage form comprising preparing a compound according to claim 11
and mixing said compound, optionally in combination with another
active pharmaceutical ingredient, with pharmaceutical excipient.
Description
FIELD OF THE INVENTION
[0001] The present invention relates in general to the field of
organic chemistry and in particular to the preparation of
substituted biphenyls, in particular to
4-halomethyl-2'-halobiphenyl and their use as intermediates in
preparation of angiotensin II antagonists. The invention also
relates to halo and organometal intermediates for preparing
telmisartan. Further the invention relates to use of in line
analytics. In addition, the invention relates to the process for
preparing pharmaceutical composition and/or dosage form comprising
the process for preparing said biphenyls or intermediates. The
embodiments of the present invention can be beneficially applied
also for preparing a medicament.
BACKGROUND OF THE INVENTION
[0002] Angiotensin II antagonists ("sartans") are efficient active
compounds with biological activity which has proved useful for the
treatment of hypertension. Most of commercially available sartans
contain biphenyl moiety substituted with 5-tetrazolyl or carboxy
group on the position 2' (Formula 1, X is COOH or
5-tetrazolyl).
##STR00001##
[0003] Telmisartan or salt or ester thereof (TLM, Formula 2) known
from EP 502314 and which can be prepared in accordance with this
invention is used as a pharmaceutical compound alone or in
combination with pharmaceutically acceptable carrier for treatment
of hypertension in human or animal and functions as angiotensin II
antagonists.
##STR00002##
[0004] 2'-halo-4-methylbiphenyls (Formula 3, X.dbd.Cl, Br, I) are
potential starting materials for the synthesis of biphenyl type
sartans but they have not found an application in industry due to
inefficient or expensive synthesis. Known procedures use Suzuki and
Heck couplings which need for industry unfriendly boron and tin
compounds, Ullmann reaction (Chem. Rev. 2002, 102, 1359-1469) give
low yields and coupling of Grignard intermediates require
significant amounts of starting materials (Org. Lett. 2000, 2,
3675-3677). The later reaction was exercised using
1,2-dihalobenzene, 4-halotoluene in the presence of magnesium and
iodine for quenching the Grignard intermediate wherein
1,2-dihalobenzene, 4-halotoluene and iodine were used in the ratio
of 1:2:3, which is not economically favorable for industrial
application.
##STR00003##
[0005] There is a need for efficient synthesis of biphenyl class of
sartans especially for carboxy group containing derivatives such as
telmisartan.
DISCLOSURE OF THE INVENTION
[0006] An aspect of the invention is a process for obtaining
2'-halo-4-methylbiphenyls, in which a 4-halotoluene is reacted with
a 1,2-dihalobenzene in the presence of magnesium, lithium, zinc,
cobalt or copper and optionally a catalyst, wherein less than 1
molar excess of 4-halotoluene in regard to 1,2-dihalobenzene is
used, and arisen organometal intermediates are quenched by
elemental halogen. Preferably less than 0.9 molar excess,
particularly less than 0.2 molar excess of 4-halotoluene in regard
to 1,2-dihalobenzene is used. Proportionally for each 1 mol of
1,2-dihalobenzene used in the reaction less than 2.9 mol;
particularly from 1 to 2 mol, preferably 1 mol of elemental halogen
is used to quench the organometal intermediate. The reaction is
carried out in ether solvent or in a mixture of aprotic solvents
comprising ether. Halo is selected from iodo, bromo or chloro.
[0007] Another aspect of the invention is a process for the
synthesis of telmisartan, losartan, irbesartan, candesartan,
olmesartan, valsartan or tasosartan or salt, ester or amide
thereof, comprising preparing 4'-halomethyl-2-halo-biphenyl
according to above aspect and converting it to said compound.
[0008] In another aspect the invention is a process for obtaining
3'-(2'-halo-biphenyl-4-ylmethyl)-1,7'-dimethyl-2'-propyl-1H,3'H-[2,5']bib-
enzoimidazolyl (TLMH) comprising coupling
2-(1-propyl)-4-methyl-6-(1'-methylbenzimidazole-2-yl)benzimidazole
and 4'-halomethyl-2-halo-biphenyl.
[0009] In a further aspect the invention is a process for obtaining
telmisartan characterized in that
3'-(2'-halo-biphenyl-4-ylmethyl)-1,7'-dimethyl-2'-propyl-1H,3'H-[2,5']bib-
enzoimidazolyl is converted to organometallic compound (TLMM) and
said organometallic compound is further reacted with formic acid
ester or amide, such as N,N-dimethylformamide, alkyl formate, and
oxidized, or with carbon dioxide. Specifically said conversion is
done with magnesium to Grignard reagent, or with Grignard reagent
by halogen/metal-exchange reaction to another Grignard reagent, or
with zinc to organozinc reagent; or preferably said conversion is
done with lithium to organolithium reagent, or with organolithium
reagent by halogen/metal-exchange reaction to another organolithium
reagent; Halo is selected from iodo, bromo or chloro, specifically
iodo.
[0010] Another aspect of the invention is use of formula TLMM for
the synthesis of telmisartan or salt, ester or amide thereof.
[0011] In yet another aspect the invention is a compound of formula
4.
##STR00004##
[0012] Another aspect of the invention is use of compound
4'-halomethyl-2-halo-biphenyl for the preparation of other sartans,
such as losartan, irbesartan, candesartan, olmesartan, valsartan,
tasosartan, salt, ester or other derivative thereof, or other
compounds, that can be derived from the
4'-halomethyl-2-halo-biphenyl, wherein halo is selected from iodo,
bromo or chloro and 4'-halomethyl-2-halo-biphenyl is not
4'-bromomethyl-2-iodo-biphenyl or
4'-bromomethyl-2-chloro-biphenyl.
[0013] Further aspect of the invention is in line analytic used to
monitor the mentioned reactions and single components (reactants,
intermediates, product and impurities) and/or for adjustment of
reaction times or reaction temperatures in the said reactions.
[0014] Additional aspect of the present invention is a process for
obtaining a pharmaceutical composition and/or dosage form
comprising preparing telmisartan or salt thereof according above
aspects; or obtaining 2'-halo-4-methylbiphenyls according to above
aspects, and converting it to telmisartan; or preparing
telmisartan, losartan, irbesartan, candesartan, olmesartan,
valsartan, tasosartan or salt, ester or amide thereof according to
above aspects, and mixing it, optionally in combination with
another active pharmaceutical ingredient, with pharmaceutical
excipient.
[0015] The present invention provides also the aspect of use of any
of the aforementioned aspects for preparing a medicament.
DETAILED DESCRIPTION OF THE INVENTION
[0016] Surprisingly it has been found that
2'-halo-4-methylbiphenyls can be obtained in a simple one-pot
two-step technical process, in yields that are industrially
applicable and competitive in which a 4-halotoluene is reacted with
a 1,2-dihalobenzene in the presence of magnesium, lithium, zinc,
cobalt or copper, and optionally a catalyst selected from a
transition metal compound, preferably a manganese, cobalt or copper
compound, wherein less than 1, particularly less than 0.9 molar,
particularly less than 0.2 molar excess of 4-halotoluene with
regard to 1,2-dihalobenzene is used, that for each mol of
1,2-dihalobenzene, from 1.0 to 1.9, particularly from 1.0 to 1.2
mol 4-halotoluene is used, more particularly from 1.05 to 1.15 mol,
and arisen organometal intermediates are quenched proportionally
for each 1 mol of 1,2-dihalobenzene by less than 2.9 mol,
particularly 1-2 mol, about 1 mol of elemental halogen.
[0017] The catalyst optionally used can be a palladium, copper,
manganese, ruthenium, chromium, nickel compound, or the like.
[0018] Suprisingly it was noted that when the molar excess of
4-halotoluene with regard to 1,2-dihalobenzene is less than 1,
preferably less than 0.9, more preferably less than 0.2, it
significantly improves the reaction yield. The reason might be that
the organometal reaction is a complex reaction and its yield
depends on the ratio of reactants. In the case of the prior art
ratio, when it was for 1,2-dihalobenzene to 4-halotoluene 1:2, the
high excess of starting reactants like 4-halotoluene could induce
transmetalation. Metalated 1,2-dihalobenzene could produce
symmetric dimeric products in one side while liberated
4-halotoluene could consume more metal or produce symmetric dimeric
products with prepared 4-metalated toluene on the other side. Such
side reaction may considerably reduce yield and quality. Thus,
reducing the molar excess of the 4-halotoluene in the metalo
reaction surprisingly improved utility of the reaction in the
industry. Further, it was unexpectedly observed that less halogen
is needed to sufficiently quench the reaction, when the ratio of
the starting reagents is changed.
[0019] The present invention provides a process for obtaining
2'-halo-4-methylbiphenyl in which 1 to less than 2 eq. of
4-halotoluene is dissolved in an aprotic solvent, which may be
selected from tetrahydrofuran, methyltetrahydrofuran, diethylether,
diisopropylether, methyl tertiary butyl ether, dibutyl ether or
diphenyl ether and the solution is maintained at about 15.degree.
C. to 80.degree. C., preferably at room temperature. 4-halotoluene
can be selected from p-bromotoluene, p-chlorotoluene or
p-iodotoluene. 2 to 5 eq of metal is added and stirred for about 5
to 180 minutes. By the term metal there is contemplated any
embodiment capable of forming organometal intermediates such as, e.
g. magnesium, lithium or zinc. To thus prepared mixture one adds 1
eq. of 1,2-dihalobenzene dissolved in up to in the said solvent
dropwise at 15.degree. C. to 80.degree. C., preferably at 50 to
60.degree. C. during 1 min to 5 hours, such as during 2 hours and
stirred at same temperature for 1 to 48 hours. Dihalobenzene can be
selected from 1-bromo-2-chlorobenzene, 1-chloro-2-iodobenzene,
1-bromo-2-iodobenzene, 1,2-dibromobenzene, or 1,2-diiodobenzene. To
the solution of thus obtained 4'-methyl-biphenyl-2-ylmetal halide
in the said solvent 1 to 5 eq of elemental halogen is added at
15.degree. C. to 80.degree. C., preferably at room temperature.
4'-methyl-biphenyl-2-ylmetal halide can be any appropriate
organometal compound such as, e. g.
4'-methyl-biphenyl-2-ylmagnesium halide, wherein halide may be
iodide, bromide or chloride, preferably bromide. Elemental halogen
is selected from iodine (I.sub.2) or bromine (Br.sub.2) or chlorine
(Cl.sub.2). The mixture is stirred for minimum 5 minutes. The
remaining halogen is reduced with aqueous solution of NaHSO.sub.3
or Na.sub.2S.sub.2O.sub.3. After work-up with water and an apolar
solvent which may be selected from esters, ethers, chlorinated
solvents and hydrocarbons preferably from aliphatic hydrocarbons
such as n-hexane, n-pentane, n-heptane, cyclohexane,
methylcyclohexane are added. The phases are separated and the
organic phase is evaporated. The product is for example purified
with LPLC chromatography. Mobile phase is n-hexane, stationary
phase is silica gel 60. The fractions are followed by TLC method
and collected. The main fractions are evaporated to give
2-halo-4'methyl-biphenyl in yield off at least 60%.
[0020] In a more specific but preferred example 1.1 eq of
4-bromotoluene is dissolved in 5 to 7 times bigger volume of
tetrahydrofuran and the solution is maintained at room temperature.
2.5 eq of Mg is added and stirred for at least 30 minutes. To thus
prepared mixture one adds 1 eq of 1-bromo-2-chlorobenzene diluted
by the same volume of tetrahydrofurane dropwise at 55.degree. C.
during 2 hours and stirred at same temperature for 1 to 3 hours. To
the solution of thus obtained 4'-methyl-biphenyl-2-ylmagnesium
bromide in tetrahydrofuran 1 eq of iodine (I.sub.2) is added and
the reaction is worked up as described above.
[0021] The employment of excess of only 0.1 eq of 4-halotoluene
dramatically improves the yield, which exceeds in this specific
example 60%. Furthermore, only 1 eq of halogen was sufficient to
quench the reaction, which lasts 3 hours at most. The procedure is
a great improvement of known literature procedures (Org. Lett.
2000, 2, 3675-3677) which takes 14 hours to react and uses over two
times excess of 4-halotoluene and three times excess of halogen to
achieve comparable yields.
[0022] In additional reactions obtained 2-halo-4'methyl-biphenyl is
halogenated in dichloromethane yielding
4'-halomethyl-2-halo-biphenyl. Specific compounds thus prepared are
4'-bromomethyl-2-bromo-biphenyl, 4'-iodomethyl-2-iodo-biphenyl,
4'-iodomethyl-2-bromo-biphenyl, 4'-iodomethyl-2-chloro-biphenyl,
4'-chloromethyl-2-iodo-biphenyl, 4'-chloromethyl-2-bromo-biphenyl,
4'-chloromethyl-2-chloro-biphenyl. In one embodiment, said
4'-halomethyl-2-halo-biphenyl can be reacted with
2-(1-propyl)-4-methyl-6-(1'-methylbenzimidazole-2-il)benzimidazole
(PMB), to afford TLMH.
[0023] In a specific embodiment the invention also provides for
coupling of 2-halo-4'-bromomethyl-biphenyl and
2-(1-propyl)-4-methyl-6-(1'-methylbenzimidazole-2-il)benzimidazole,
which is performed but not limited as follows: 10-25 mL of
sulfolane (tetramethylene sulfone) or N,N-dimethylacetamide or
N-methyl-2-pyrrolidone or dimethyl sulfoxide is charged to the
flask. 0.85 g of
2-(1-propyl)-4-methyl-6-(1'-methylbenzimidazole-2-il)benzimidaz-
ole and 0.38 g of strong base such as KtBuO or appropriate amount
of NaOH, KOH, LiOH, Na.sub.2CO.sub.3, K.sub.2CO.sub.3, NaHCO.sub.3
or KHCO.sub.3 are added. The mixture is brought to the temperature
of about 25.degree. C.-45.degree. C. to dissolve all the
components. The solution is then brought to the temperature of
about 5.degree. C. to 25.degree. C. and from 1 to 1.2 equivalents
of 2-halo-4'-bromomethyl-biphenyl in 5 to 20 mL of solvent is added
during 0.5-5 hours. The reaction mixture is stirred at the same
temperature for additional 0-5 hours. 40 mL of demineralised water
and 35 mL of ethyl acetate are added. The phases are separated. The
EtOAc phase is washed several times with saturated water solution
of NaCl. The solvent is evaporated and 4 mL mixture of EtOAc and
acetone is added. The suspension is stirred for 15 minutes to 5
hours. The precipitate is filtered off and dried to give TLMH.
[0024] In a preferred example telmisartan is prepared from the
intermediate
3'-(2'-halo-biphenyl-4-ylmethyl)-1,7'-dimethyl-2'-propyl-1H,3'H-[2,5']bib-
enzoimidazolyl (TLMH) by introducing C-1 synthon in high oxidation
state in one-pot two-step procedure on the position 2'. Scheme 1
represents the synthesis of TLMH.
##STR00005## ##STR00006##
[0025] TLMH is further converted to organometallic compound TLMM as
presented in Scheme 2 which is further reacted with formic acid
derivative such as ester or amide, preferably
N,N-dimethylformamide, or carbon dioxide in the second step as
presented in Scheme 3.
[0026] Formula 4 encompasses embodiments TLMH and TLMM, wherein
TLMH is halo substituted on the 2' position of
3'-(biphenyl-4-ylmethyl)-1,7'-dimethyl-2'-propyl-1H,3'H-[2,5']bibenzoimid-
azolyl, representing
3'-(2'-halo-biphenyl-4-ylmethyl)-1,7'-dimethyl-2'-1H,3'H-[2,5']bibenzoimi-
dazolyl, and TLMM is Li, MgX or ZnX substituted on the 2' position
of the biphenyl part of
3'-(biphenyl-4-ylmethyl)-1,7'-dimethyl-2'-propyl-1H,3'H-[2,5']bibenzoimid-
azolyl, wherein X is selected from iodo, bromo or chloro. Metals
for creating organometallic intermediate are selected from alkali,
earth-alkali, transition metals or lantanides. In created
organometallic compounds of type TLM-Met, TLM-MetX or
(TLM).sub.2-Met TLM means decarboxytelmisartan radical, Met is
metal (monovalent or bivalent respectively) and X is chloro, bromo
or iodo. Preferred metals are lithium, magnesium or zinc.
##STR00007##
##STR00008##
[0027] Organomagnesium compounds are prepared as Grignard reagents
of type TLM-MgX (X.dbd.Cl, Br, I) by reacting magnesium with the
halo compound TLMH, optionally in the presence of a catalyst,
preferably iodine or 1,2-dibromoethane. Alternatively Grignard
intermediates TLM-MgX are prepared with halogen/metal-exchange
reaction with another commercial Grignard reagent.
[0028] Organolithium reagent of type TLM-Li is preferably prepared
from TLMH by halogen/metal-exchange reaction with elemental lithium
or by translithiation with another organolithium compound
preferably with carbyllithium, preferably aryllithium or
alkyllithium, more preferably phenyllithium or butyllithium, most
preferably butyllithium.
[0029] Organozinc reagents of type TLM-ZnX (X is selected from
iodo, bromo or chloro) can be prepared from TLMH and zinc or its
derivative but are preferably prepared from organometal
intermediates of type TLM-MgX or TLM-Li and anhydrous zinc
halogenide selected from chloride, bromide or iodide.
[0030] Organometallic compound is preferably prepared in situ in
anhydrous solvents preferably selected from ethers and is converted
to telmisartan by bubbling of carbon dioxide or stirred with a
solid carbon dioxide (dry ice) at temperature from -50.degree. C.
to boiling point, preferably at room temperature for 5 min to 10 h
preferably 2 to 4 hours.
[0031] In a special but not limited example a solution of TLMH in
an above mentioned ether solvent is treated with alkyl lithium
preferably butyl lithium at the temperature bellow 0.degree. C.,
preferably bellow -40.degree. C. to provide halogen lithium
exchange. Following that the prepared solution is bubbled with
carbon dioxide gas (CO.sub.2) or stirred with a solid carbon
dioxide (dry ice) for 5 to 300 minutes. The diluted HCl or
NH.sub.4Cl is added and telmisartan is precipitated and filtered
off. The cake is washed with water and telmisartan isolated.
[0032] In the alternative reaction the above described
organometallic intermediates are treated by formic acid derivatives
such as esters and amides, preferably N,N-dimethylformamide to give
telmisartan aldehyde precursor which can be further oxidized to
telmisartan.
[0033] In a special but not limited example the above described
organolithium solution is quenched with N,N-dimethylformamide at
the temperature bellow 0.degree. C., preferably slowly rising
temperature from bellow -40.degree. C. to room temperature to
obtain
3'-(2'-formyl-biphenyl-4-ylmethyl)-1,7'-dimethyl-2'-propyl-1H,3'H-[2,5']b-
ibenzoimidazolyl which is converted to telmisartan by oxidation
with manganese like manganese (IV) oxide and potassium
permanganate, chromium (VI) oxidants like sodium chromate or
chromium (VI) oxide adducts, peroxides like hydrogene peroxide in
water, low alkanoic acids or alcohols or organic peroxides like
alkyl peroxides or carboxylic peroxoacids or higher oxidation state
chlorine compounds like metal or organic hypochlorites or sodium
chlorate (III) or bromo compounds like bromine, N-bromosuccinimide,
inorganic peroxo salts like potassium peroxodisulfate, potassium
peroxomonosulfate known under tradename OXONE.RTM. or sodium
perborate or silver oxyde or oxygene or the like. Preferably sodium
chlorate (III) with hydrogene peroxide is used.
[0034] In another embodiment the invention also provides for simple
preparation of other angiotensin II antagonists like losartan,
irbesartan, candesartan, olmesartan and valsartan, which have a
residue such as heterocycle or amino acid derivative via methylene
linked to a biphenyl and which include a tetrazole substituent on
biphenyl in-lieu of carboxylic acid. For those
4'-halomethyl-2-halo-biphenyl is coupled with appropriate residue,
which could be prepared or obtained as defined by general knowledge
and well-known to the person versed in the art, and biphenylic halo
substituent converted into tetrazole as shown in Scheme 4.
[0035] Base can be selected from inorganic base such as, sodium
hydroxide, potassium hydroxide and the like. R.sub.3 in the Scheme
4 represents alkyl.
##STR00009##
[0036] The overall processes of present invention utilize series of
Grignard reactions which allows unification of solvents and solvent
conditions, furthermore the concentration of components in the
reaction mixture is in an aspect of the invention advantageously
monitored by the use of in line Fourier transform infrared
spectroscopy (FTIR) analytic, thus allowing the adjustment of
reaction times and temperatures in real-time or very near
real-time. By using a FTIR spectrophotometer it is possible to
explore the kinetics of the organic chemical reactions that are not
photoinitiated and do not have convenient ultraviolet-visible
spectral features. FTIR analytic allows to measure rates, reaction
process, end points and mechanisms of the reactions in a solution.
FTIR analytics can be employed by using fiber-optic probe attached
to a spectrometer, installed to the reaction mixture container,
wherein the probe or a spectrometer can be controlled by a desktop
computer running supporting software. FTIR is especially
suitable
[0037] In line analytic (ATR FTIR probe) is used to monitor the
reactions and single components (reactants, intermediates, product
and impurities) and/or to adjust reaction time or reaction
temperatures. The background of air is used. The following peaks
(heights calculated to single baseline) are monitored: 3242
cm.sup.-1, 2339 cm.sup.-1, 1509 cm.sup.-1, 1486 cm.sup.-1, 1405
cm.sup.-1, 1393 cm.sup.-1, 1227 cm.sup.-1, 1039 cm.sup.-1, 1034
cm.sup.-1, 883 cm.sup.-1, 880 cm.sup.-1, 826 cm.sup.-1, 802
cm.sup.-1, 783 cm.sup.-1, 752 cm.sup.-1, 764 cm.sup.-1, 721
cm.sup.-1, 694 cm.sup.-1. The 1.sup.st and 2.sup.nd derivative
tools a subtraction tools are used to isolate the component peaks
from the IR spectrum of the reaction mixture.
[0038] The peaks at 783 cm.sup.-1 and 1227 cm.sup.-1 represent the
p-toluyl magnesium halide, the peaks at 1035 cm.sup.-1 and 880
cm.sup.-1 represent the ether complex of a Grignard and the peak at
695 cm.sup.-1 is intermediate (1-halophenyl-2-magnesium halide).
The reaction is finished when the peak at 695 cm.sup.-1
disappears.
[0039] Thus, another embodiment of the present invention is the
process for sartan compounds or 2'-halo-4-methylbiphenyls
comprising organometal intermediates, wherein the reaction or
single component is monitored with in line FTIR analytics.
2'-halo-4-methylbiphenyls can be prepared according to process
comprising reacting 4-halotoluene with a 1,2-dihalobenzene in the
presence of metal such as magnesium, lithium or zinc, which already
suffices for introduction of in line FTIR analytics. Especially
when arisen organometal intermediate is quenched by elemental
halogen, providing additional signal to be monitored during the
reaction. The inline FTIR analytics can be efficiently utilized
also in the processes for obtaining sartans such as telmisartan,
losartan, irbesartan, valsartan, olmesartan, candesartan, where the
use of organometal intermediates in obtaining
2'-halo-4-methylbiphenyls precedes or is subsequently followed by
reaction steps that afford sartan. For example telmisartan or salt
thereof can be prepared by a process comprising converting
3'-(2'-halo-biphenyl-4-ylmethyl)-1,7'-dimethyl-2'-propyl-1H,3'H-[2,5']bib-
enzoimidazolyl to organometallic compound and further reacting said
organometallic compound with formic acid derivative or carbon
dioxide. As an example N,N-dimethylformamide, alkylformiate can be
used as a formic derivative. Specifically,
3'-(2'-halo-biphenyl-4-ylmethyl)-1,7'-dimethyl-2'-propyl-1H,3'H-[2,5']bib-
enzoimidazolyl can be converted with magnesium to Grignard reagent,
or with Grignard reagent by halogen/metal-exchange reaction to
another Grignard reagent, or with lithium to organolithium reagent,
or with organolithium reagent by halogen/metal-exchange reaction to
another organolithium or with zinc to organozinc reagent. The
utilization of in line FTIR analytics in the process for preparing
sartans in combination with said organometallic compound has an
advantageous effect, as it enables to accurately lead the synthesis
process in the controllable and efficient manner. Further
embodiment of the invention is a container comprising reaction
mixture in combination with a FTIR probe, wherein the reaction
mixture comprises organometal intermediate or metal reagent and the
desired end product of the reaction is selected from the group
consisting of telmisartan, losartan, irbesartan, candesartan,
olmesartan, valsartan and tasosartan, or intermediate, salt, ester
or amide thereof. Organometal intermediate or metal reagent can be
Grignard reagent, lithium, organolithium reagent, zinc, organozinc
reagent, or the like.
[0040] Additionally or alternatively the redox electrode is used to
trace the concentration of iodine, bromine or chlorine.
[0041] Additional embodiment of the invention is a process for
obtaining a pharmaceutical composition and/or dosage form
comprising obtaining 2'-halo-4-methylbiphenyls, wherein
4-halotoluene is reacted with a 1,2-dihalobenzene in the presence
of magnesium, lithium, zinc, cobalt or copper, and optionally a
catalyst, wherein less than 1 molar excess of 4-halotoluene in
regard to 1,2-dihalobenzene is used, and converting it to
telmisartan; or preparing telmisartan or salt thereof comprising
converting
3'-(2'-halo-biphenyl-4-ylmethyl)-1,7'-dimethyl-2'-propyl-1H,3'H-[2,5']bib-
enzoimidazolyl to organometallic compound and further reacting said
organometallic compound with formic acid ester and amide and
further oxidation of aldehyde, or with carbon dioxide; and mixing
it, optionally in combination with another active pharmaceutical
ingredient, with pharmaceutical excipient. The processes of
preparing telmisartan, wherein organometal intermediate or metal
reagent is applied, can comprise subsequent steps of mixing said
telmisartan, optionally together with another active pharmaceutical
ingredient, with pharmaceutical excipient. Organometal intermediate
can be for example Grignard reagent, organolithium reagent or
organozinc reagent. Metal reagent can be for example lithium or
zinc. Suitable pharmaceutical excipients are for example binders
(e.g. polyvinylpyrrolidon), disintegrators (e.g. starch, cellulose
derivatives), surfactants (e.g. sodium laurylsulphate), pH
balancing agents (e.g. citric acid, sodium hydroxide, meglumine),
fillers (e.g. mannitol, cellulose derivatives), vehicles (e.g.
water, glycerol, alcohol), flavors, colorants (e.g. titanium
dioxide). The reason for introducing additional active
pharmaceutical ingredient into pharmaceutical composition and/or
dosage form together with telmisartan is to achieve synergistic
effect of both active pharmaceutical ingredients, or having a goal
of addressing two indications simultaneously, or to reduce side
effects of the first active pharmaceutical ingredient with the
simultaneous or consecutive application of the second active
pharmaceutical ingredient, or the like. For example, another active
pharmaceutical ingredient can be hydrochlorothiazide, amlodipine or
ramipril. The technology used for preparing pharmaceutical
formulations and/or dosage forms can be any one known to the person
skilled in the pharmaceutical technology. Telmisartan, excipients
and optionally another active pharmaceutical ingredient can be
simply mixed as powders or dissolved in a suitable solvent.
Granulation techniques can be applied to improve the handling
properties of said formulation. Dry granulation with compacting or
briquetting can be undertaken to prime the granulation mass for
tabletting. Similarly, wet granulation with adding or spraying
granulation liquid onto particles, powders or already dry granules
of compounds can be used to aid formulation of the compounds in the
dosage form. Granulation techniques can be used to improve
flowability, compressibility, especially when the mass is intended
to be used for tabletting. Granulation can also reduce dusting and
can determine the dissolution properties. Such properties are
desired not only with tablets but also in capsules. It is known,
that dosage forms can be in a form of tablets, capsules, pellets,
granules, powders, solutions, or the like, wherein solid dosage
forms can further be coated or layered. Apparatus such as mixer,
tabletting machine, extrudor, granulator can be used in preparing
the pharmaceutical composition and/or dosage form. Any process
according to the present invention, compound of formula 4, any of
the aforementioned 4'-halomethyl-2-halo-biphenyl, or preparing the
pharmaceutical composition and/or dosage form can be used for
preparing a medicament, meaning that said process of preparing
pharmaceutical composition and/or dosage form is expanded to
embrace necessary steps for preparing a medicament. Said steps can
include determination of the right amount of active pharmaceutical
ingredient in the pharmaceutical composition and/or dosage form,
packaging, or combining the pharmaceutical composition and/or
dosage form with a product leaflet.
[0042] The following examples illustrate the present invention and
are not intended to limit the scope of the invention.
EXAMPLE 1
##STR00010##
[0044] Formation of Grignard Reagent
[0045] 60 mL of tetrahydrofuran is charged to the flask. 9 g (52.6
mmol) of p-bromotoluene is added and the solution is maintained at
20.degree. C. 3.0 g (125 mmol) of Mg is added and stirred for
minimal 30 minutes.
[0046] Coupling
[0047] 9.3 g (48.7 mmol) of 1-bromo-2-chlorobenzene in 5 mL of THF
is added into the prepared reaction mixture of p-toluyl magnesium
bromide and remaining magnesium at 55.degree. C. in 2 hours and
stirred at 55.degree. C. for 2 hours.
[0048] Quenching
[0049] The prepared solution of 2-magnesium
bromide-4'-methyl-biphenyl is cooled to room temperature, and 20 mL
of tetrahydrofuran with further 12.3 g (48.7 mmol) of iodine
(I.sub.2) are added. The mixture is agitated for minimum 5 minutes.
The remaining iodine in neutralised with aqueous solution of
NaHSO.sub.3. 70 mL of demineralised water and 50 mL of n-hexane are
added. The phases are separated and the upper (n-hexane) phase is
evaporated. The 15.6 g of yellowish liquid is obtained.
[0050] The product is purified with LPLC chromatography. Mobile
phase is n-hexane, stationary phase is silicagel 60. The fractions
are collected. The main fractions are evaporated. 8.6 g (60%) of
2-iodo-4'methyl-biphenyl (colourless liquid) is obtained.
[0051] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.: 2.56 (s, 3H),
7.13 (dt, J=7.5 Hz, J=2.0 Hz, 1H), 7.39 (s, 4H), 7.44 (dd, J=7.6
Hz, J=1.9 Hz, 1H), 7.47-7.52 (m, 1H), 8.09 (dd, J=7.9 Hz, J=1.0 Hz,
1H). .sup.13C NMR (75 MHz, CDCl.sub.3) .delta.: 146.4, 141.2,
139.3, 137.1, 130.0, 129.0, 128.5, 128.5, 128.0, 98.8, 21.2.
EXAMPLE 2
Bromination of 2-iodo-4'-methyl-biphenyl
##STR00011##
[0053] 20 mL of dichloromethane (DCM) is charged to the flask. 0.73
g of N-bromosuccinimide (NBS), 0.08 g of 2,2'-azoisobutyronitrile
(AIBN), 18 pL of Br.sub.2 and 0.9 g of 2-iodo-4'-methyl-biphenyl
are added. The reaction is carried out under reflux temperature for
minimum 2 hours and the flask is lighted all the time. The reaction
is quenched with aqueous solution of Na.sub.2S.sub.2O.sub.3. The
phases are separated and the lower DCM phase is washed with
demineralised water one more time. The DCM phase is evaporated and
4 mL of n-hexane is charged and stirred at room temperature for 30
minutes. The suspension is then cooled to 0.degree. C. and
filtered. The cake is washed with 2 mL of solvent. 0.6 g of white
crystals of 4'-bromomethyl-2-iodo-biphenyl is obtained.
[0054] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.: 4.58 (s, 2H),
7.06 (dt, J=7.6 Hz, J=1.8 Hz, 1H), 7.31 (dd, J=7.7 Hz, J=1.8 Hz,
1H), 7.35 (d, J=8.2 Hz, 2H), 7.40 (dt, J=7.4 Hz, J=1.2 Hz, 1H),
7.48 (d, J=8.2 Hz, 2H), 7.98 (dd, J=7.9 Hz, J=1.1 Hz, 1H). .sup.13C
NMR (75 MHz, CDCl.sub.3) .delta.: 145.8, 144.1, 139.5, 137.0,
130.0, 129.6, 128.9, 128.6, 128.1, 98.3, 33.2.
EXAMPLE 3
Bromination of 2-iodo-4'-methyl-biphenyl
[0055] 15.9 g of 2-iodo-4'-methyl-biphenyl is dissolved in 140 mL
of dichloromethane (DCM) than 0.7 g of 2,2'-azoisobutyronitrile
(AIBN), and slowly first 1,83 mL and after 1 h additional 1.14 ml
of Br.sub.2 are added. The reaction is carried out under reflux
temperature for 5 hours and the flask is lighted all the time. The
reaction is quenched with aqueous solution of
Na.sub.2S.sub.2O.sub.3. The phases are separated and the lower DCM
phase is washed with demineralised water one more time. The DCM
phase is evaporated and 40 mL of n-hexane is charged and stirred at
40.degree. C. for 30 minutes. The suspension is then cooled to
0.degree. C. and filtered. The cake is washed with 15 mL of hexane
and 11,0 g of white crystals of 4'-bromomethyl-2-iodo-biphenyl is
obtained.
[0056] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.: 4.58 (s, 2H),
7.06 (dt, J=7.6 Hz, J=1.8 Hz, 1H), 7.31 (dd, J=7.7 Hz, J=1.8 Hz,
1H), 7.35 (d, J=8.2 Hz, 2H), 7.40 (dt, J=7.4 Hz, J=1.2 Hz, 1H),
7.48 (d, J=8.2 Hz, 2H), 7.98 (dd, J=7.9 Hz, J=1.1 Hz, 1H). .sup.13C
NMR (75 MHz, CDCl.sub.3) .delta.: 145.8, 144.1, 139.5, 137.0,
130.0, 129.6, 128.9, 128.6, 128.1, 98.3, 33.2.
EXAMPLE 4
Alkylation of
(2-(1-propyl)-4-methyl-6-(1'-methylbenzimidazole-2-il)benzimidazole)
##STR00012##
[0058] 15 mL of sulfolane (tetramethylene sulfone) is charged to
the flask. 0.85 g of PMB
(2-(1-propyl)-4-methyl-6-(1'-methylbenzimidazole-2-il)benzimidazole)
and 0.38 g of potassium tert-butoxide are added. The mixture is
heated above 30.degree. C. to dissolve all the components. The
solution is than cooled down to 15.degree. C. and 1.07 g of
4'-bromomethyl-2-iodo-biphenyl in 5 mL of solvent is added slowly
during 45 minutes. The reaction mixture is stirred at the same
temperature for additional 2 hours. 40 mL of demineralised water
and 35 mL of EtOAc (ethyl acetate) are added. The phases are
separated. The upper EtOAc phase is washed several times with
saturated water solution of NaCl. The solvent is evaporated and 4
mL mixture of EtOAc and acetone is added. The suspension is stirred
for 30 minutes at room temperature. The suspension is filtered and
0.94 g of white crystals of
3'-(2'-iodo-biphenyl-4-ylmethyl)-1,7'-dimethyl-2'-propyl-1H,3'H-[2,5']bib-
enzimidazolyl are obtained.
[0059] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.: 1.06 (t, J=7.4
Hz, 3H), 1.84-1.92 (m, 2H), 2.95 (t, J=7.8 Hz, 2H), 3.81 (s, 3H),
5.46 (s, 2H), 7.03 (ddd, J=7.9 Hz, J=7.4 Hz, J=1.8 Hz, 1H), 7.13
(d, J=8.0 Hz, 2H), 7.23-7.54 (m, 9H), 7.77-7.83 (m, 1H), 7.94 (dd,
J=7.9 Hz, J=1.1 Hz, 1H).
EXAMPLE 5
Synthesis of Telmisartan
##STR00013##
[0061] 0.5 g of
3'-(2'-iodo-biphenyl-4-ylmethyl)-1,7'-dimethyl-2'-propyl-1H,3'H-[2,5']bib-
enzoimidazolyl is dissolved in 10 mL of THF and the solution is
cooled to temperature of -60.degree. C. to -70.degree. C. 0.58 mL
of 1.6 M solution of butyl lithium in hexane is slowly added to the
solution and the reaction mixture is stirred for 15 min at the same
temperature.
[0062] Separately dried powdered CO.sub.2 was suspended in
approximately 20 ml of THF and the prepared solution of
(4'-((1,7'-dimethyl-2'-propyl-1H,3'H-2,5'-bibenzo[d]imidazol-3'-yl)methyl-
)biphenyl-2-yl)lithium is slowly added not extending the
temperature above -40.degree. C. After finishing the addition the
mixture is allowed to be warmed to -10.degree. C. and stirred for 1
h. The diluted HCl is then added and precipitated telmisartan is
filtered of. The cake is washed with water. 0.4 g of crude
telmisartan
(2-[4-[[4-methyl-6-(1-methylbenzoimidazol-2-yl)-2-propyl-benzoimidazol-1--
yl]methyl]phenyl]benzoic acid) is obtained.
EXAMPLE 6
Formation of
3'-(2'-formyl-biphenyl-4-ylmethyl)-1,7'-dimethyl-2'-propyl-1H,3'H-[2,5']b-
ibenzoimidazolyl and synthesis of telmisartan
##STR00014##
[0064] To a suspension of
3'-(2'-iodo-biphenyl-4-ylmethyl)-1,7'-dimethyl-2'-propyl-1H,3'H-[2,5']bib-
enzoimidazolyl (460 mg) in toluene (13 mL) is added 1.6 M BuLi in
hexane (0.56 mL) within 60 min at room temperature. After 60 h,
dimethylformamide (DMF; 0.2 mL) is added all at once and the
mixture is stirred for an additional 24 h. Water (4 mL) is added,
the phases are separated and extracted 4 times with 9 mL of ethyl
acetate. Combined organic extracts are dried over MgSO.sub.4 and
evaporated under reduced pressure to obtain 230 mg of TLMA as crude
amorphous product.
[0065] A solution of 156 mg of NaClO.sub.2.4H.sub.2O in 1 mL of
water was added dropwise by canilla to a stirred mixture of
4'-[(2-n-propyl-4-methyl-6-(1-methyl-imidazol-4-yl)-benzimidazol-1-yl)met-
hyl]-biphenyl-2-carboxaldehyde (230 mg) in 1 mL of acetonitrile,
0.16 ml of 10 solution of NaH.sub.2PO.sub.4 in water and 0.23 mL of
30% H.sub.2O.sub.2 at the temperature 10.degree. C. pH of the
mixture was adjusted to 2 with concentrated hydrochloric acid.
Stirring was continued for 1.5 h at room temperature. Reaction
mixture was poured in 1.2 mL of water, stirred for 15 minutes,
product filtered, washed with water and dried in vacuo to yield 210
mg of telmisartan.
* * * * *